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Daniela Matuozzo; Estelle Talouarn; Astrid Marchal; Jeremy Manry; Yoann Seeleuthner; Yu Zhang; Alexandre Bolze; Matthieu Chaldebas; Baptiste Milisavljevic; Peng Zhang; Adrian Gervais; Paul Bastard; Takaki Asano; Lucy Bizien; Federica Barzaghi; Hassan Abolhassani; Ahmad Abou Tayoun; Alessandro Aiuti; Ilad Alavi Darazam; Luis Allende; Rebeca Alonso-Arias; Andres Augusto Arias; Gokhan Aytekin; Peter Bergman; Simone Bondesan; Yenan Bryceson; Ingrid Bustos; Oscar Cabrera-Marante; Sheila Carcel; Paola Carrera; Giorgio Casari; Khalil Chaibi; Roger Colobran; Antonio Condino-Neto; Laura Covill; Loubna El Zein; Carlos Flores; Peter Gregersen; Marta Gut; Filomeen Haerynck; Rabih Halwani; Selda Hancerli; Lennart Hammarstrom; Nevin Hatipoglu; Adem Karbuz; Sevgi Keles; Christele Kyheng; Rafael Leon-Lopez; Jose Luis Franco; Davood Mansouri; Javier Martinez-Picado; Ozge Metin Akcan; Isabelle Migeotte; Pierre-Emmanuel Morange; Guillaume Morelle; Andrea Martin-Nalda; Giuseppe Novelli; Antonio Novelli; Tayfun Ozcelik; Figen Palabiyik; Qiang Pan-Hammarstrom; Rebeca Perez de Diego; Laura Planas-Serra; Daniel Pleguezuelo; Carolina Prando; Aurora Pujol; Luis Felipe Reyes; Jacques Riviere; Carlos Rodriguez-Gallego; Julian Rojas; Patrizia Rovere-Querini; Agatha Schluter; Mohammad Shahrooei; Ali Sobh; Pere Soler-Palacin; Yacine Tandjaoui-Lambiotte; Imran Tipu; Cristina Tresoldi; Jesus Troya; Diederik van de Beek; Mayana Zatz; Pawel Zawadzki; Saleh Zaid Al-Muhsen; Hagit Baris-Feldman; Manish Butte; Stefan Constantinescu; Megan Cooper; Clifton Dalgard; Jacques Fellay; James Heath; Yu-Lung Lau; Richard Lifton; Tom Maniatis; Trine Mogensen; Horst von Bernuth; Alban Lermine; Michel Vidaud; Anne Boland; Jean-Francois Deleuze; Robert Nussbaum; Amanda Kahn-Kirby; France Mentre; Sarah Tubiana; Guy Gorochov; Florence Tubach; Pierre Hausfater; Isabelle Meyts; Shen-Ying Zhang; Anne Puel; Luigi Notarangelo; Stephanie Boisson-Dupuis; Helen Su; Bertrand Boisson; Emmanuelle Jouanguy; Jean-Laurent Casanova; Qian Zhang; Laurent Abel; Aurelie Cobat.
Preprint in English | medRxiv | ID: ppmedrxiv-22281221


BackgroundWe previously reported inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity in 1-5% of unvaccinated patients with life-threatening COVID-19, and auto-antibodies against type I IFN in another 15-20% of cases. MethodsWe report here a genome-wide rare variant burden association analysis in 3,269 unvaccinated patients with life-threatening COVID-19 (1,301 previously reported and 1,968 new patients), and 1,373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. A quarter of the patients tested had antibodies against type I IFN (234 of 928) and were excluded from the analysis. ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI:1.5-528.7, P=1.1x10-4), in analyses restricted to biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70 [95%CI:1.3-8.2], P=2.1x10-4). Adding the recently reported TYK2 COVID-19 locus strengthened this enrichment, particularly under a recessive model (OR=19.65 [95%CI:2.1-2635.4]; P=3.4x10-3). When these 14 loci and TLR7 were considered, all individuals hemizygous (n=20) or homozygous (n=5) for pLOF or bLOF variants were patients (OR=39.19 [95%CI:5.2-5037.0], P=4.7x10-7), who also showed an enrichment in heterozygous variants (OR=2.36 [95%CI:1.0-5.9], P=0.02). Finally, the patients with pLOF or bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10-5). ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.

Preprint in English | medRxiv | ID: ppmedrxiv-22273206


BackgroundThe antiviral efficacy of remdesivir is still controversial. We aimed at evaluating its clinical effectiveness in hospitalised patients with COVID-19, with indication of oxygen and/or ventilator support. Following prior publication of preliminary results, here we present the final results after completion of data monitoring. MethodsIn this European multicentre, open-label, parallel-group, randomised, controlled trial (DisCoVeRy, NCT04315948; EudraCT2020-000936-23), participants were randomly allocated to receive usual standard of care (SoC) alone or in combination with remdesivir, lopinavir/ritonavir, lopinavir/ritonavir and IFN-{beta}-1a, or hydroxychloroquine. Adult patients hospitalised with COVID-19 were eligible if they had clinical evidence of hypoxemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzyme, severe chronic kidney disease, any contra-indication to one of the studied treatments or their use in the 29 days before randomization, or use of ribavirin, as well as pregnancy or breast-feeding. Here, we report results for remdesivir + SoC versus SoC alone. Remdesivir was administered as 200 mg infusion on day 1, followed by once daily infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. Treatment assignation was performed via web-based block randomisation stratified on illness severity and administrative European region. The primary outcome was the clinical status at day 15 measured by the WHO 7-point ordinal scale, assessed in the intention-to-treat population. FindingsBetween March 22nd, 2020 and January 21st, 2021, 857 participants were randomised to one of the two arms in 5 European countries and 843 participants were included for the evaluation of remdesivir (control, n=423; remdesivir, n=420). At day 15, the distribution of the WHO ordinal scale was as follow in the remdesivir and control groups, respectively: Not hospitalized, no limitations on activities: 62/420 (14.8%) and 72/423 (17.0%); Not hospitalized, limitation on activities: 126/420 (30%) and 135/423 (31.9%); Hospitalized, not requiring supplemental oxygen: 56/420 (13.3%) and 31/423 (7.3%); Hospitalized, requiring supplemental oxygen: 75/420 (17.9%) and 65/423 (15.4%); Hospitalized, on non-invasive ventilation or high flow oxygen devices: 16/420 (3.8%) and 16/423 (3.8%); Hospitalized, on invasive mechanical ventilation or ECMO: 64/420 (15.2%) and 80/423 (18.9%); Death: 21/420 (5%) and 24/423 (5.7%). The difference between treatment groups was not statistically significant (OR for remdesivir, 1.02, 95% CI, 0.62 to 1.70, P=0.93). There was no significant difference in the occurrence of Serious Adverse Events between treatment groups (remdesivir, n=147/410, 35.9%, versus control, n=138/423, 32.6%, p=0.29). InterpretationRemdesivir use for the treatment of hospitalised patients with COVID-19 was not associated with clinical improvement at day 15. FundingEuropean Union Commission, French Ministry of Health, DIM One Health Ile-de-France, REACTing, Fonds Erasme-COVID-ULB; Belgian Health Care Knowledge Centre (KCE), AGMT gGmbH, FEDER "European Regional Development Fund", Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. Remdesivir was provided free of charge by Gilead.

Preprint in English | medRxiv | ID: ppmedrxiv-22271545


ObjectivesHealthcare workers (HCWs) are at higher risk of contracting coronavirus disease-19 (COVID-19) than the general population. This study assessed the roles of various exposures and personal protective equipment (PPE) use on that risk for HCWs working in primary care, long-term-care facilities (LTCFs) or hospitals. MethodsWe conducted a matched case-control (1:1) study (10 April-9 July 2021). Cases (HCWs with confirmed COVID-19) and controls (HCWs without any COVID-19-positive test or symptoms) recruited by email were invited to complete an online questionnaire on their exposures and PPE use. Questions covered the 10 days preceding symptom onset for cases (or testing if asymptomatic) or inclusion for controls. ResultsA total of 4152 matched cases and controls were included. The multivariable conditional logistic regression analysis retained exposure to an infected person outside work (adjusted odds ratio, 19.9 [95% confidence intervaI, 12.4-31.9]), an infected colleague (2.26 [1.53-3.33]) or COVID-19 patients (2.37 [1.66-3.40]), as independent predictors of COVID-19 in HCWs, while partial or complete immunization was protective. Eye protection (0.57 [0.37-0.87]) and wearing a gown (0.58 [0.34-0.97]) during COVID-19 patient care were protective, while wearing an apron slightly increased the risk of infection (1.47 [1.00-2.18]). N95-respirator protection was comparable to that of surgical masks. Results were consistent across healthcare-facility categories. ConclusionsHCWs were more likely to get COVID-19 in their personal sphere than during occupational activities. Our results suggest that eye protection for HCWs during patient care should be actively promoted.

Preprint in English | medRxiv | ID: ppmedrxiv-20249038


BackgroundThe systemic antibody responses to SARS-CoV-2 in COVID-19 patients has been extensively studied. However, much less is known about the mucosal responses in the upper airways at the site of initial SARS-CoV-2 replication. Local antibody responses in the nasopharyngeal epithelium, that are likely to determine the course of infection, have not been analysed so far nor their correlation with antibody responses in serum. MethodsThe IgG and IgA antibody responses were analysed in the plasma as well as in nasopharyngeal swabs (NPS) from the first four COVID-19 patients confirmed by RT-qPCR in France. Two were pauci-symptomatic while two developed severe disease. Taking advantage of a comprehensive series of plasma and nasopharyngeal samples, we characterized their antibody profiles from the second week post symptoms onset, by using an in-house ELISA to detect anti-SARS-CoV-2 Nucleoprotein (N) IgG and IgA. ResultsAnti-N IgG and IgA antibodies were detected in the NPS of severe patients. Overall, the levels of IgA and IgG antibodies in plasma and NPS appeared specific to each patient. ConclusionsAnti-N IgG and IgA antibodies are detected in NPS, and their levels are related to antibody levels in plasma. The two patients with severe disease exhibited different antibody profiles that may reflect different disease outcome. For the pauci-symptomatic patients, one showed a low anti-N IgG and IgA response in the plasma only, while the other one did not exhibit overt serological response.

Preprint in English | medRxiv | ID: ppmedrxiv-20194860


Objective: We aimed to estimate the risk of infection in Healthcare workers (HCWs) following a high-risk exposure without personal protective equipment (PPE). Methods: We conducted a prospective cohort in HCWs who had a high-risk exposure to SARS-CoV-2-infected subject without PPE. Daily symptoms were self-reported for 30 days, nasopharyngeal swabs for SARS-CoV-2 RT-PCR were performed at inclusion and at days 3, 5, 7 and 12, SARS-CoV-2 serology was assessed at inclusion and at day 30. Confirmed infection was defined by positive RT-PCR or seroconversion, and possible infection by one general and one specific symptom for two consecutive days. Results: Between February 5th and May 30th, 2020, 154 HCWs were enrolled within 14 days following one high-risk exposure to either a hospital patient (70/154; 46.1%) and/or a colleague (95/154; 62.5%). At day 30, 25.0% had a confirmed infection (37/148; 95%CI, 18.4%; 32.9%), and 43.9% (65/148; 95%CI, 35.9%; 52.3%) had a confirmed or possible infection. Factors independently associated with confirmed or possible SARS-CoV-2 infection were being a pharmacist or administrative assistant rather than being from medical staff (adjusted OR (aOR)=3.8, CI95%=1.3;11.2, p=0.01), and exposure to a SARS-CoV-2-infected patient rather than exposure to a SARS-CoV-2-infected colleague (aOR=2.6, CI95%=1.2;5.9, p=0.02). Among the 26 HCWs with a SARS-CoV-2-positive nasopharyngeal swab, 7 (26.9%) had no symptom at the time of the RT-PCR positivity. Conclusions: The proportion of HCWs with confirmed or possible SARS-CoV-2 infection was high. There were less occurrences of high-risk exposure with patients than with colleagues, but those were associated with an increased risk of infection.

Preprint in English | medRxiv | ID: ppmedrxiv-20191759


Background. Molecular assays on nasopharyngeal swabs remain the cornerstone of COVID-19 diagnostic. Despite massive worldwide efforts, the high technicalities of nasopharyngeal sampling and molecular assays, as well as scarce resources of reagents, limit our testing capabilities. Several strategies failed, to date, to fully alleviate this testing process (e.g. saliva sampling or antigen testing on nasopharyngeal samples). We assessed the performances of a new ELISA microplate assay quantifying SARS-CoV-2 nucleocapsid antigen (N-antigen) in serum or plasma. Methods. The specificity of the assay, determined on 63 non-COVID patients, was 98.4% (95% confidence interval [CI], 85.3 to 100). Performances were determined on 227 serum samples from 165 patients with RT-PCR confirmed SARS-CoV-2 infection included in the French COVID and CoV-CONTACT cohorts. Findings. Sensitivity was 132/142, 93.0% (95% CI, 84.7 to 100), within the first two weeks after symptoms onset. A subset of 73 COVID-19 patients had a serum collected within 24 hours following or preceding a positive nasopharyngeal swab. Among patients with high nasopharyngeal viral loads, Ct value below 30 and 33, only 1/50 and 4/67 tested negative for N-antigenemia, respectively. Among patients with a negative nasopharyngeal RT-PCR, 8/12 presented positive N-antigenemia. The lower respiratory tract was explored for 6/8 patients, showing positive PCR in 5 cases. Interpretation. This is the first demonstration of the N-antigen antigenemia during COVID-19. Its detection presented a robust sensitivity, especially within the first 14 days after symptoms onset and high nasopharyngeal viral loads. These findings have to be confirmed with higher representation of outpatients. This approach could provide a valuable new option for COVID-19 diagnosis, only requiring a blood draw and easily scalable in all clinical laboratories.